The purpose of this project is to study the long-term health effects of drugs, especially therapeutic agents, as they may relate to carcinogenicity. In addition, the patterns of occurrence of multiple primary cancer are evaluated in terms of implications for etiologic research. Because many studies of radiation carcinogenesis involve the evaluation of second cancers following radiotherapy for a primary cancer, it is often convenient to evaluate, simultaneously, the effects of chemotherapeutic agents. Populations studied include patients treated in randomized clinical trials, patients reported to cancer registries in the United States and other countries, and patients treated at several large institutions. In addition to the systematic study of therapeutic drugs, occasionally it is possible to evaluate other drug exposures in populations studied for other reasons. A study of patients given methyl-CCNU as adjuvant therapy for gastrointestinal cancer provided clear dose-response evidence that nitrosoureas are leukemogenic in man. Alkylating agents to treat childhood cancer were associated with an increased risk of leukemia and bone cancer. Women with breast cancer who received chemotherapy are at an increased risk of leukemia. Among ovarian cancer patients, treatment with melphalan appears three times more leukemogenic than with cyclophosphamide. Commonly used drugs were not found to be related to thyroid cancer. Cancer patients have a 31% increased risk of developing a second primary 49% among 30-year survivors. Smoking may be causally related to cervical cancer.